tbuckley/cabot-search huggingface dataset:
Association of pneumococcal carriage in infants with the risk of carriage among their contacts in Nha Trang, Vietnam: A nested cross-sectional survey
Authors: George Qian, Michiko Toizumi, Sam Clifford, Lien Thuy Le, Tasos Papastylianou, Catherine Satzke, Billy Quilty, Chihiro Iwasaki, Noriko Kitamura, Mizuki Takegata, Minh Xuan Bui, Hien Anh Thi Nguyen, Duc Anh Dang, Albert Jan van Hoek, Lay Myint Yoshida, Stefan Flasche
Journal: PLoS Medicine (2022)

Infants are at highest risk of pneumococcal disease. Their added protection through herd effects is a key part in the considerations on optimal pneumococcal vaccination strategies. Yet, little is currently known about the main transmission pathways to this vulnerable age group. Hence, this study investigates pneumococcal transmission routes to infants in the coastal city of Nha Trang, Vietnam.In October 2018, we conducted a nested cross-sectional contact and pneumococcal carriage survey in randomly selected 4- to 11-month-old infants across all 27 communes of Nha Trang. Bayesian logistic regression models were used to estimate age specific carriage prevalence in the population, a proxy for the probability that a contact of a given age could lead to pneumococcal exposure for the infant. We used another Bayesian logistic regression model to estimate the correlation between infant carriage and the probability that at least one of their reported contacts carried pneumococci, controlling for age and locality. In total, 1,583 infants between 4 and 13 months old participated, with 7,428 contacts reported. Few infants (5%, or 86 infants) attended day care, and carriage prevalence was 22% (353 infants). Most infants (61%, or 966 infants) had less than a 25% probability to have had close contact with a pneumococcal carrier on the surveyed day. Pneumococcal infection risk and contact behaviour were highly correlated: If adjusted for age and locality, the odds of an infant's carriage increased by 22% (95% confidence interval (CI): 15 to 29) per 10 percentage points increase in the probability to have had close contact with at least 1 pneumococcal carrier. Moreover, 2- to 6-year-old children contributed 51% (95% CI: 39 to 63) to the total direct pneumococcal exposure risks to infants in this setting. The main limitation of this study is that exposure risk was assessed indirectly by the age-dependent propensity for carriage of a contact and not by assessing carriage of such contacts directly.In this study, we observed that cross-sectional contact and infection studies could help identify pneumococcal transmission routes and that preschool-age children may be the largest reservoir for pneumococcal transmission to infants in Nha Trang, Vietnam.
Abstract 4055: First in class multifunctional non classical antifolates inhibits thymidylate synthase and extends survival in pancreatic cancer model
Authors: Maria V. Guijarro, Patrick C. Kellish, Peter E. Dib, Nicholas G. Paciaroni, Akbar Nawab, Jacob Andring, Lidia Kulemina, Nicholas V. Borrero, Carlos Modenutti, Richard L. Bennett, Daniil Shabashvili, Jonathan D. Licht, Robert McKenna, Adrian Roitberg, Robert W. Huigens, Frederic J. Kaye, Maria Zajac-Kaye
Journal: Cancer Research (2022)

Abstract Thymidylate synthase (TS) inhibitors are an integral component of chemotherapy regimens for difficult to treat cancer subtypes. Despite initial therapeutic benefit, current inhibitors induce TS overexpression or alter folate transport metabolism feedback pathways that tumor cells exploit for drug resistance. Here we report a small molecule TS inhibitor that exhibits i) enhanced antitumor activity as compared to current fluoropyrimidines and antifolates without inducing TS overexpression, ii) is structurally distinct from classical antifolates, iii) extends survival in a pancreatic tumor mouse model, iv) and is well tolerated with equal efficacy using either intraperitoneal or oral administration. Mechanistically, we confirm the compound is a multifunctional non classical antifolate and through a series of analogues identify structural features allowing direct TS inhibition while also maintaining the ability to inhibit dihydrofolate reductase (DHFR). Collectively, this work identifies new non classical antifolate inhibitors that optimize inhibition of thymidylate biosynthesis with a favorable safety profile highlighting potential for enhanced cancer therapy. Citation Format: Maria V. Guijarro, Patrick C. Kellish, Peter E. Dib, Nicholas G. Paciaroni, Akbar Nawab, Jacob Andring, Lidia Kulemina, Nicholas V. Borrero, Carlos Modenutti, Richard L. Bennett, Daniil Shabashvili, Jonathan D. Licht, Robert McKenna, Adrian Roitberg, Robert W. Huigens, Frederic J. Kaye, Maria Zajac-Kaye. First in class multifunctional non classical antifolates inhibits thymidylate synthase and extends survival in pancreatic cancer model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4055.
Abstract 2406: Mechanism of mSin1 regulation of cell migration
Authors: Shile Huang, Lei Liu, Yan Luo
Journal: Cancer Research (2022)

Abstract Studies have shown that mSin1, a major component of mTORC2, plays an important role in tumor cell migration and invasion as well as cancer metastasis. However, how mSin1 regulates cell migration is poorly understood. In this study, we found that knockout of mSin1 suppressed cell spreading and migration in mouse embryo fibroblasts (MEFs). Similarly, knockdown of mSin1 also inhibited cell spreading and migration in rhabdomyosarcoma (Rh30) and cervical cancer (HeLa) cells. Furthermore, we observed that knockout or knockdown of mSin1 reduced the activities of the small GTPases (RhoA and Rac1) in the cells. Ectopic expression of constitutively active Rac1, but not RhoA, partially attenuated the reduced cell spreading and migration induced by mSin1 deficiency. In addition, depletion of mSin1 remarkedly inhibited the phosphorylation of focal adhesion proteins, including focal adhesion kinase (FAK) at Tyr397 and paxillin at Tyr118 in the cells. The results suggest that mSin1 controls cell spreading and migration at least partly by mediating the activity of Rac1 and the phosphorylation of FAK. (Supported by the Feist-Weiller Cancer Center, LSU Health Sciences Center, Shreveport, LA, USA) Citation Format: Shile Huang, Lei Liu, Yan Luo. Mechanism of mSin1 regulation of cell migration [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2406.
Abstract 1276: Nucleolin has prognostic value in neuroblastoma patients
Authors: Davide Cangelosi, Chiara Brignole, Veronica Bensa, Roberto Tamma, Fabiana Malaguti, Barbara Carlini, Enzo Calarco, Patrizia Perri, Domenico Ribatti, Nuno A. Fonseca, Joao N. Moreira, Alessandra Eva, Loredana Amoroso, Massimo Conte, Alberto Garaventa, Angela R. Sementa, Maria V. Corrias, Mirco Ponzoni, Fabio Pastorino
Journal: Cancer Research (2022)

Abstract Background: Neuroblastoma (NB) represents the most frequent form of extracranial solid tumor of infants, responsible for 15% of childhood cancer deaths. Nucleolin (NCL) prognostic value in NB was here investigated. Methods: NCL protein expression was evaluated in NB patients at diagnosis and after induction chemotherapy. NCL mRNA prognostic value was first assessed in a cohort of 20 stage M NB patients and confirmed in the MultiPlatform786 including 786 NB patients of all stages. Overall and event-free survival curves were plotted by Kaplan-Meier method and compared by log-rank test. Findings: NCL protein resulted significantly overexpressed in NB tumors compared to the non tumoral counterpart, and higher in stage M compared to stage L patients. In the stage M cohort and in MultiPlatform786 dataset, patients with high NCL mRNA expression revealed a significant lower survival probability than those with low NCL expression. In MultiPlatform786 dataset, NCL mRNA expression was significantly higher in patients with age &amp;gt;18 months, in stage M and in MYCN amplified tumors than in patients with age ˂18 months and in stage L or MS and with MYCN non amplified tumors, respectively. Multivariate analysis suggested NCL has a significant prognostic value even in the model adjusted for established prognostic markers. NCL significantly stratified patients with age &amp;lt;18 and age &amp;gt;18, stage M, &amp;gt;18 months and stage M tumor, stages L or MS, and with MYCN not amplified. A significant correlation between NCL and MYCN, MYC, and TERT was found in two independent datasets. Gene set enrichment analysis revealed a significant positive enrichment of MYC target genes and genes involved in telomerase maintenance. NCL protein resulted down-modulated after chemotherapy, in association with morphological features of neuroblastic differentiation. Interpretation: NCL is a novel and independent prognostic marker for NB. Funding: IMH-EuroNanoMed II-2015 (ER-2015-2360441-Eranet) and AIRC IG n. 24397 to PF. Citation Format: Davide Cangelosi, Chiara Brignole, Veronica Bensa, Roberto Tamma, Fabiana Malaguti, Barbara Carlini, Enzo Calarco, Patrizia Perri, Domenico Ribatti, Nuno A. Fonseca, Joao N. Moreira, Alessandra Eva, Loredana Amoroso, Massimo Conte, Alberto Garaventa, Angela R. Sementa, Maria V. Corrias, Mirco Ponzoni, Fabio Pastorino. Nucleolin has prognostic value in neuroblastoma patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1276.
Abstract 5945: Gnetin C for chemoprevention and chemotherapy of prostate cancer
Authors: Gisella Campanelli, Rabab Al Deabel, Anand Puaar, Prashanth Parupathi, Amee Adhvaryu, Avinash Kumar, Anait S. Levenson
Journal: Cancer Research (2022)

Abstract Prostate cancer is common among aging men. No cancer treatment is provided during active surveillance for prostate cancer. Targeted nutritional interception may prove to be the most appropriate chemoprevention for intermediate- and high-risk patients. Here, for the first time, we investigate the efficacy of Gnetin C, a resveratrol-dimer found abundantly in melinjo (Gnetum gnemon) plant that is characterized with improved pharmacokinetics compared to other stilbenes, in a transgenic mouse model of prostate cancer. We have generated two prostate-specific mouse models, one overexpressing MTA1 on the background of Pten heterozygosity (R26MTA1; Pten+/f), and the other overexpressing MTA1 on the background of Pten loss (R26MTA1; Ptenf/f). Chemoprevention design included Gnetin C- dietary supplementation in the high-risk model while the therapeutic design included i.p. administration in the more aggressive R26MTA1; Ptenf/f genotype. Our results show that while MTA1 cooperates with PTEN deficiency to accelerate PIN development by increasing MTA1-associated signaling, Gnetin C intervention combats the progression of prostate cancer. We show that mice treated with Gnetin C (7 mg/kg bw, daily i.p.) exhibited more favorable histopathology with decreased severity and number of PIN foci (41.23% reduction) accompanied by reduced proliferation (Ki67, 57.43% reduction), angiogenesis (CD31, 86.91% reduction), AR (31.57% reduction), and MTA1 (27.94% reduction). Ongoing chemopreventive studies with four different diets [Control-diet; Gnetin C high dose (70 mg/kg diet); Gnetin C low dose (35 mg/kg diet); and pterostilbene (70 mg/kg diet)] are in progress. Altogether, these data provide an evidence for efficacy of Gnetin C in blocking prostate cancer progression and reveal its potential for novel chemopreventive and therapeutic implications in prostate cancer.Supported by NCI/NIH R15CA216070 to ASL Citation Format: Gisella Campanelli, Rabab Al Deabel, Anand Puaar, Prashanth Parupathi, Amee Adhvaryu, Avinash Kumar, Anait S. Levenson. Gnetin C for chemoprevention and chemotherapy of prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5945.
An Asymptomatic Verrucous Plaque on the Right Temple of an Adolescent Girl
Authors: Zi-Jia Dai, Li He, Tong-Yun Liu
Journal: JAMA Dermatology (2022)

An adolescent girl presented with an asymptomatic slightly reddish verrucous plaque on the right temple; the skin lesion was nail sized when first noticed 1½ years ago, then gradually developed over the previous 8 months. What is your diagnosis?
Abstract 5621: NCG-X mouse: A novel animal model to evaluate preclinical studies of humanized erythroid reconstitution without irradiation
Authors: Tingting Gu, Cunxiang Ju, Hongyan Sun, Xiang Gao, MingKun Zhang, Weiwei Yu, Mengting Wang, Shuai Li, Shuai Li, Huiyi Wang, Jing Zhao
Journal: Cancer Research (2022)

Abstract Hematopoietic stem cell (HSC) transplantation is an adoptive immunotherapy for treating malignant hematopoietic cancers and autoimmune disorders. Preclinical studies of such novel therapies require animal models that enable and sustain human erythrocyte reconstitution. Existing mouse models typically require irradiation to remove mouse HSCs from the bone marrow prior to human immune system reconstitution. Irradiation adversely affects the health of the animal by promoting necrosis and apoptosis of gastrointestinal, neural and muscle tissues, which can lead to wasting, infection, and even death. An irradiation-free mouse model for human erythroid reconstitution is in urgent need. KIT proto-oncogene receptor tyrosine kinase, also known as c-KIT, is an important cell surface marker expressed in both mouse and human HSCs, multipotent progenitors (MPP), and common myeloid progenitors (CMP). KIT signaling plays a key role in cell survival, proliferation, and differentiation. Alterned forms of this protein have been shown to be associated with some types of cancer. Point mutation of Val831Met is known to cause macrocytic anemia. We speculate that mice with this mutation experience spontaneous anemia and inhibited HSC function, which would support human erythroid reconstitution without irradiation. NCG-X mouse was generated based on this hypothesis, building upon the severe immunodeficient NCG generated by GemPharmatech years ago. This new strain of mice are deficient of T/B/NK cells with functional inhibition of HSCs. Here, we report that NCG-X supports human HSC transplantation without radiation, enabling complete avoidance of adverse effects on animal health. When compared with irradiated NCG mice, NCG-X mice are able to not only rebuild the human immune system, but also enable human erythroid cells to reconstruct the bone marrow for a prolonged period of time after engraftment: 16 and 30 weeks post-engraftment have been assayed. Though reduced red blood cells and hemoglobin have been observed, 30 weeks post-engraftment enables consistent support from the start to the finish of the preclinical phase. In conclusion, NCG-X provides an improved and preclinical relevant mouse model for therapeutic development of leukemia, thalassemia, other types of blood diseases and autoimmune diseases. Citation Format: Tingting Gu, Cunxiang Ju, Hongyan Sun, Xiang Gao, MingKun Zhang, Weiwei Yu, Mengting Wang, Shuai Li, Shuai Li, Huiyi Wang, Jing Zhao. NCG-X mouse: A novel animal model to evaluate preclinical studies of humanized erythroid reconstitution without irradiation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5621.
Abstract 2049: A novel, rapid, sensitive, and reproducible <i>in vivo</i> platform to assess efficacy and toxicity of bispecific antibodies
Authors: Jiwon Yang, Jing Jiao, Kyle Draheim, Danying Cai, Michael A. Brehm, Leonard D. Shultz, Dale L. Greiner, Mingshan Cheng, James G. Keck
Journal: Cancer Research (2022)

Abstract A bispecific T-cell engager (BiTE) enhances the antitumor capabilities of T-cells by directing them to recognize a tumor-specific antigen. Several BiTEs are currently in clinical trials, and there is one FDA-approved BiTE for cancer therapy at the moment. However, one of the biggest challenges BiTE is currently facing is cytokine release syndrome (CRS). While most patients have mild flu-like symptoms, some patients experience a severe inflammatory syndrome, which could ultimately cause multi-system organ failure and death. Thus, the key is to accurately predict the risk-benefit ratio of each individual before starting the treatment. Unfortunately, there is no reliable in vitro or in vivo model to predict the toxicity and efficacy of BiTE at the moment. Additionally, one of the most challenging factors for pre-clinical evaluation of BiTEs for toxicity and efficacy is the inherent differences among patients’ immune systems. Here, we developed an in vivo PBMC-humanized mouse model that can evaluate both toxicity and efficacy of BiTE and other immune-oncology therapeutics in each individual mouse. The platform was validated using an anti-CD28 superagonist (TGN1412), which none of the pre-clinical in vitro assays and in vivo studies, including non-human primates, executed before clinical trials were able to predict the observed clinical toxicities. This model uses luciferase-tagged human B-cell lymphoma Raji tumor cells to allow the measurement of tumor burden and response to treatment, along with toxicity simultaneously. In addition, we showed that this platform can determine individual PBMC donor differences, and potential adverse drug combinations and drug dose-response with efficacy and safety on individual PBMC donors. The model we developed can potentially be used as a predictive and reproducible platform to identify patient, cancer, and therapy combinations at risk for developing CRS. This model will also help to optimize the therapeutic drug dose range to improve the safety profile of BiTE and other immune-oncology drugs. We believe this platform will greatly benefit not only the scientific community but potentially cancer patients as well. Citation Format: Jiwon Yang, Jing Jiao, Kyle Draheim, Danying Cai, Michael A. Brehm, Leonard D. Shultz, Dale L. Greiner, Mingshan Cheng, James G. Keck. A novel, rapid, sensitive, and reproducible in vivo platform to assess efficacy and toxicity of bispecific antibodies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2049.
Abstract 107: Reciprocal Sox2 regulation by SMAD1 and SMAD3 is critical for anoikis resistance and metastasis in ovarian cancer
Authors: Zainab M. Shonibare, Mehri Monavarian, Kathleen O'Connell, Diego Altamore, Abigail Shelton, Shubham Mehta, Renata Jaskula-Sztul, Rebecca Phaeton, Andrew Berchuck, Andrew B. Nixon, Rebecca Arend, Nam Y. Lee, Ryan Miller, Nadine Hempel, Karthikeyan Mythreye
Journal: Cancer Research (2022)

Abstract The tumor ascites environment is enriched with cytokines and growth factors especially members of the Transforming Growth Factor-β (TGF-β) family, that play crucial roles in modulating anoikis sensitivity and consequently metastatic progression in ovarian cancer. Here, we demonstrated for the first-time significant broad dichotomy between these TGF-β members: BMPs and TGF-β/activin and their regulated SMADs in this process. We previously reported BMP9/GDF2 to be in low to undetected levels in ovarian cancer patient-derived ascites and promoted anoikis resistance in both breast and ovarian cancer cell lines. We have now identified additional BMPs -BMP2, BMP4 and BMP9 as promoting anoikis sensitivity in a spectrum of ovarian cancer cells. Conversely, we found TGF-βs (1 and 2) to be in much higher expression and demonstrated that TGF-β and activin promoted anoikis resistance in ovarian cancer. Hence, in an attempt to identify genes downstream of BMPs that may provide anoikis resistance, transcriptomics was performed leading to the identification of Sox2, a developmental gene with prior established roles in OVCA, as being significantly downregulated in response to BMP9. We further uncovered Sox2 to be reciprocally regulated by anoikis-promoting BMPs (2, 4 and 9) and anoikis suppressing TGF-β and activin A. Our findings highlight a novel contrasting SMAD dependent regulation of Sox2 as a central node for controlling tumor cell survival in ovarian cancers demonstrating a subset of BMPs as a therapeutic strategy in cancer. The studies presented here begin to elucidate the mechanisms of reciprocal epigenetic regulation of Sox2 by BMP and TGF-β/activin in the context of ovarian cancer, which is the most lethal gynecologic malignancy in women due to peritoneal metastatic spread. Citation Format: Zainab M. Shonibare, Mehri Monavarian, Kathleen O'Connell, Diego Altamore, Abigail Shelton, Shubham Mehta, Renata Jaskula-Sztul, Rebecca Phaeton, Andrew Berchuck, Andrew B. Nixon, Rebecca Arend, Nam Y. Lee, Ryan Miller, Nadine Hempel, Karthikeyan Mythreye. Reciprocal Sox2 regulation by SMAD1 and SMAD3 is critical for anoikis resistance and metastasis in ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 107.
Impact of T-cell immunity on chemotherapy response in childhood acute lymphoblastic leukemia
Authors: Yizhen Li, Xu Yang, Yu Sun, Zhenhua Li, Wenjian Yang, Bensheng Ju, John Easton, Deqing Pei, Cheng Cheng, Shawn Lee, Ching-Hon Pui, Jiyang Yu, Hongbo Chi, Jun J. Yang
Journal: Blood (2022)
Austral birds offer insightful complementary models in ecology and evolution
Authors: Jörn Theuerkauf, Camila P. Villavicencio, Nicolas M. Adreani, Alfredo Attisano, Adrian Craig, Pietro B. D’Amelio, Roman Gula, Alan T.K. Lee, Lucía Mentesana, Petra Quillfeldt, Veronica Quirici, René Quispe, Rodrigo A. Vásquez, John C. Wingfield, Juan F. Masello
Journal: Trends in Ecology & Evolution (2022)